While most cases of Alzheimer's disease (AD) occur sporadically, some are inherited in an autosomal dominant fashion and known as familial AD (FAD). These cases share many clinical and pathological features found in sporadic AD but exhibit a much earlier age of onset. Despite their relative rarity, their known genetic etiology makes them ideal for modeling in transgenic animals and it is hoped that their study will provide clues to the molecular pathways that are disturbed in the more common sporadic disease. Mutations in the presenilin-1 (PS1) gene are the most commonly recognized cause of early onset FAD. Although less studied than senile plaques and neurofibrillary tangles, AD is also accompanied by microvascular pathology. We have observed an age related vascular pathology in two lines of transgenic mice harboring PS1 FAD mutations that resembles the microvascular pathology in human cases and vascular pathology is also found in amyloid precursor protein (APP) FAD mutant mice. The pathology in the PS1 mice is associated with abnormal expression of several extracellular matrix (ECM) related proteins and early thickening of the vascular basal laminae. We have also found that endothelial cells that lack PS1 overexpress fibronectin as well as have increased levels of the 1521 integrin, the principle fibronectin receptor. These observations thus suggest a role for PS1 in the regulation of ECM production in endothelial cells. This application will address three key questions related to these observations. Firstly we will address how the absence of PS1 affects production of fibronectin with the specific hypothesis that it does so by regulating integrin related signaling. Secondly we will address the question of whether PS1 as well as APP FAD mutants alter ECM related protein production and examine the molecular basis of the microvascular pathology observed in PS1 and APP FAD mutant transgenic mice. Finally we will address the question of whether altered ECM production may be an early event in the microvascular pathology of human cases of sporadic AD. PUBLIC HEALTH RELEVANCE: With the aging of the veteran population diseases such as AD are becoming of increasing importance to the mission of the VA. While the clinical features and pathology of the AD are well known, there are no effective treatments and the pathophysiology of the disorder is only incompletely understood. The present application with its focus on the origins of the vascular pathology found in AD will advance understanding of the pathophysiological basis of AD associated vascular pathology which may lead to the identification of new therapeutic targets for the disease.